Pancreas after Kidney Transplantation

After three decades of controversy surrounding the therapeutic validity of pancreas transplantation, the procedure has become accepted as the preferred treatment for patients with insulin-dependent diabetes mellitus (IDDM) and advanced diabetic nephropathy with end-stage renal disease (ESRD) and for those approaching ESRD. Vascularized pancreas transplantation is currently the only available form of autoregulating, total endocrine replacement therapy that reliably achieves an insulin-independent euglycemic state and normal glucose homeostasis, resulting in the successful management of diabetes mellitus. The trade-offs for normal glucose homeostasis are the operative risks of the pancreas transplant procedure and the need for chronic immunosuppression. Free islet grafts have the same potential, but their efficacy requires further evaluation. With improvements in organ retrieval and preservation technology, refinements in diagnostic methods and surgical techniques, advances in clinical immunosuppression and anti-infective prophylaxis, and increased experience with donor and recipient selection, success rates for pancreas transplantation have continued to improve. From 1966 through October 2000, >15,000 pancreas transplants were performed throughout the world and reported to the International Pancreas Transplant Registry (IPTR) (1). In the past decade, the majority (83%) of pancreas transplants were performed in combination with a kidney transplant [simultaneous pancreas/kidney transplants (SPKT)] for patients with ESRD attributable to diabetic nephropathy. The current 1-yr actuarial patient, kidney, and pancreas (with complete insulin independence) graft survival rates after SPKT are 95, 92, and 84%, respectively (1). Solitary pancreas transplants comprised the remaining cases, including sequential pancreas after kidney transplants (PAKT) (12%) and pancreas transplants alone (PTA) (5%) (1). Although the annual rate of pancreas transplants has steadily increased, the number of solitary pancreas transplants has increased disproportionately in recent years; in 1999, 75% of transplants were SPKT, 18% PAKT, and 7% PTA. The current 1-yr patient survival rate after solitary pancreas transplantation is 95%, and the 1-yr actuarial pancreas graft survival rates are 73% for PAKT and 70% for PTA (1). The differences in graft survival rates for SPKT, PAKT, and PTA have been attributed to increased rates of graft loss resulting from rejection and thrombosis after solitary pancreas transplantation. Pancreas transplantation should be considered an acceptable therapeutic alternative to continued insulin therapy for diabetic patients with imminent or established ESRD who have undergone or plan to undergo a kidney transplant, because the successful addition of a pancreas does not jeopardize patient survival rates, may improve kidney graft survival rates, and will restore normoglycemia (2). PAKT is advocated for diabetic patients with well functioning kidney transplants, because these patients already require chronic immunosuppression and the additional risk is primarily that of the surgical procedure (3,4). Currently, many transplant centers are experienced in performing SPKT; only a few centers have accumulated much experience with PAKT. The improved success of SPKT has prompted many centers to offer pancreas transplantation for patients with type 1 diabetes mellitus who have undergone successful kidney transplantation. PAKT increases the likelihood of more diabetic recipients receiving a pancreas transplant and eliminates many of the organ-allocation issues associated with SPKT. The increased interest in PAKT is attributable to several factors. New immunosuppressive medications have reduced acute rejection rates and enhanced pancreas graft survival rates (5). Better surgical techniques, patient selection, and immunologic monitoring have also improved short- and long-term success rates after pancreas transplantation (6). Finally, the recent decision by Medicare to reimburse providers for the procedure has eliminated the financial burden for many potential recipients. Despite these advancements, there are no clear guidelines for donor and recipient selection, immunologic monitoring, the choice of immunosuppressive agents, or the timing of PAKT. This lack has prompted the Pancreas Committee of the American Society of Transplantation to review the current status of PAKT. History and Background Dr. Richard Lillehei performed the first pancreas transplant at the University of Minnesota in 1966 (7). Pancreas transplantation was abandoned at that center in 1973, after 14 transplants had been performed with only one successful pancreas graft functioning for 1 yr. The program was resumed in 1978. Throughout the world, only 1157 pancreas transplants were performed between 1966 and 1987, with three-fourths of the transplants being performed after 1982 (8). Despite a multitude of surgical approaches for duct drainage and the use of cyclosporin A (CsA) after 1983, the 1-yr patient and pancreas graft survival rates were only 76 and 37%, respectively (8). During this early experience, it became evident that SPKT was associated with better graft survival rates than was either PAKT or PTA. Historically, major impediments to successful pancreas transplantation were the management of exocrine secretions, the inability to monitor the pancreas for rejection, and high rates of rejection, thrombosis, and pancreatitis. In the past two decades, significant improvements in the surgical and medical management of pancreas transplants have occurred. The management of pancreatic exocrine secretions improved with the development of bladder drainage, which allowed for measurement of urinary amylase levels, facilitating prediction of acute rejection episodes (9). Improvements in immunosuppression made possible a return to enteric drainage of the exocrine secretions by preventing episodes of acute rejection and eliminating the need for high-dose steroid therapy, which impaired healing of the enteric anastomosis. Finally, techniques were developed for the diagnosis of rejection via percutaneous biopsy, facilitating monitoring for rejection among recipients of either PAKT or PTA (10). Current Status As indicated in Table 1, advances in immunosuppression and surgical techniques have improved the overall results for SPKT, as reported by the IPTR (1). Some individual centers have reported >90% survival rates for pancreatic allografts at 1 yr (11–13). Although previously there was debate regarding the appropriateness of SPKT in the therapy of type 1 diabetes mellitus (14,15), excellent outcomes after SPKT are now being achieved (1,11–13,16,17). The American Society of Transplantation (18) and the American Diabetes Association (2) consider SPKT an appropriate treatment for diabetic patients with ESRD attributable to type 1 diabetes mellitus. Moreover, SPKT and PAKT are now (since July 1999) reimbursed by Medicare. Table 1 presents the results observed for PAKT in different eras, indicating that outcomes have improved with time. Notably, in every era, outcomes of PAKT lag behind those achieved with SPKT. PAKT performed after living-donor kidney transplantation has two major benefits (3,19). Living-donor transplants demonstrate the best long-term survival rates, and use of a living-donor kidney does not remove a cadaveric donor kidney from the pool of organs available for potential transplant recipients. Table 1: One-year survival results after SPKT, PAKT, and PTAaDonor Selection Donor selection and organ procurement are of paramount importance for the success of PAKT. Most heart-beating donors who have been declared brain-dead and are suitable for kidney, liver, and heart donation are also suitable for pancreas donation (Table 2). Although there is some evidence to suggest that donor hyperglycemia may have an adverse effect on initial and long-term allograft function, the presence of hyperglycemia or hyperamylasemia is not a contraindication for pancreas donation. Table 2: Cadaveric pancreas donationaIn general, ideal pancreas donors range in age from 10 to 40 yr and range in weight from 30 to 80 kg. As the results of pancreas transplantation have improved and experience has increased, previous contraindications for pancreas donation have become mere risk factors for successful outcomes (Table 2). According to IPTR data, the following variables are associated with increased risks of pancreas allograft thrombosis: (1) donor age of >40 yr, (2) cardiovascular or cerebrovascular cause of brain death, and (3) pancreas preservation time of >24 h (1). The results of anecdotal experience suggest that (1) >150% of ideal body weight or a body mass index (BMI) of >30 kg/m2 for the donor may be associated with an increased risk of early pancreas graft loss (attributable to thrombosis, pancreatitis, infection, or primary nonfunction); (2) a donor liver biopsy with >25 to 30% macrovascular steatosis may be associated with a fatty pancreas, leading to an increased risk of early graft loss; and (3) fatty infiltration of the pancreas (as opposed to peripancreatic fat) may be associated with an increased risk of early graft loss (20,21). The presence of donor obesity or a fatty pancreas may be an underappreciated cause of early graft loss after PAKT. There are currently no data available regarding the utility of donor pancreas biopsies, particularly with respect to steatosis. The importance of an experienced retrieval team for in situ assessment of pancreatic anatomic features must be emphasized. Pancreas donors may be categorized as ideal, good, or marginal. By using donor age, weight/BMI, and the cause of brain death as the three most important factors, rapid accurate assessments of the quality of the donor pancreas can usually be made before actual intraoperative assessment, which is the next most important factor. PAKT donors must be either ideal or good. If either the donor or recipient is marginal, then there is a greater likelihood of a poor outcome. Compared with SPKT, the inherent risk of thrombosis is much higher (two- to threefold) for PAKT (22). In contrast to other transplanted organs, the solitary pancreas is susceptible to thrombosis because of its low microcirculatory flow based on collateral circulation. In the absence of the antiplatelet and anticoagulative effects of uremia, PAKT recipients may be prone to vascular thrombosis. For this reason, cold ischemia should be kept to a minimum and serious consideration should be given to routine perioperative anticoagulation therapy for the recipient. Recipient Selection In the past, most pancreas transplants were performed with younger recipients. However, the most recent analysis by the IPTR indicated that >25% of the recipients in 1998 and 1999 were >44 yr of age (1). Recipient age remains a significant risk factor for death after SPKT but not PAKT. These data must be interpreted with caution, because there were fewer recipients of PAKT in the analysis. Specific selection criteria for PAKT are based on the presence of established secondary diabetic complications or hyperlabile diabetes mellitus, with adequate cardiac and renal functional reserve (23). Indications for pancreas transplantation include IDDM and the predicted ability of the patient to tolerate the operative procedure, the requisite intense immunosuppression after transplantation, and possible associated complications (Table 3). Patient selection is facilitated by a comprehensive medical evaluation before transplantation, performed by a multidisciplinary team, that confirms the diagnosis of IDDM, determines the ability of the patient to withstand the operative procedure, establishes the absence of any exclusion criteria (Table 4), and documents end-organ complications for monitoring after transplantation. The primary determinants for recipient selection are the presence of diabetic complications, the degree of nephropathy, and cardiovascular risks (Table 3). With increasing experience, previous absolute contraindications have become relative contraindications, and relative contraindications have become risk factors for pancreas transplantation (Table 4). Table 3: Indications for pancreas transplantation and eligibility guidelinesTable 4: and relative contraindications and risk factors for pancreas patients who have previously a renal from either a or cadaveric are considered potential for PAKT their are >40 with either or immunosuppression (23). If the patient is not receiving a for the kidney transplant, a of is (Table 3). of a an in the for results in a in is to factor the of the particularly because the use of a the actual of In this a of high-dose or before pancreas transplantation or may be to the effects of the on the levels, and with significant nephropathy of the previously transplanted kidney, renal because of or acute or chronic rejection, with may not be suitable recipients for PAKT. A kidney biopsy is for and monitoring of the of nephropathy after PAKT. However, there are few data on the use of the biopsy results to recipient The presence of chronic allograft nephropathy be a contraindication to PAKT for patients with renal allograft The cardiac status of must be because significant disease is not in this The cardiac evaluation should include a functional assessment, as an or in addition to is for as age of yr, diabetes mellitus for >25 yr, a a previous major attributable to vascular a of cerebrovascular or an indicated by the or cardiac (23). of previous or are not contraindications for PAKT, because excellent outcomes have been reported for patients who have undergone previous cardiac However, cardiac death, in the absence of significant heart to be a major cause of cardiac death after pancreas transplantation For this reason, a number of centers are to cardiac for these using cardiovascular and heart rate These methods may be to in before the of In general, age of yr, a of a recent and obesity of ideal body weight or of >30 are as contraindications for PAKT (Table (23). Most patients who are yr of age are acceptable for PAKT, that no significant disease is patients who are yr of age are not and must undergo cardiovascular and vascular evaluation. immunosuppressive therapy for kidney transplantation may be associated with medical complications, and these factors should be considered before PAKT. Recipient weight criteria are to those for donor recipients of and recipients of on their and body demonstrate higher rates of surgical complications after pancreas transplantation a of >30 kg/m2 is considered an absolute contraindication and a of kg/m2 is a relative contraindication for PAKT. A of with and monitoring is an important factor in patient exclusion criteria that are to transplant recipients include the presence of or recent or a recent of or and or results (Table 4). of PAKT A major for recipients with a suitable donor is to with the kidney transplant, by a pancreas transplant, or to undergo a SPKT. the results of PAKT are now approaching those of SPKT, the need for surgical procedure and enhanced immunosuppressive therapy should be the organ the time for a cadaveric donor transplant, and the increased rates these it may be to consider a living-donor kidney transplant by a cadaveric pancreas There are several factors to be considered in the timing of PAKT. some time should after the kidney transplant, to of graft function, surgical and reduced immunosuppression before pancreas transplantation. However, long-term recipients may experience significant complications secondary to diabetes mellitus and chronic immunosuppression. from the University of outcomes for pancreas transplants performed or after kidney transplantation. the PAKT pancreas transplantation after kidney transplantation, with the remaining being performed after kidney transplantation. of complications as thrombosis, exocrine and were for the two pancreas rejection rates at and graft and patient survival rates at yr for early PAKT were and for PAKT were and These were not is to transplant the cadaveric pancreas the same surgical procedure as the living-donor kidney transplantation. This requires the donor and the recipient to a suitable cadaveric pancreas However, centers this have performed a few after patients for transplantation The major of an are the of surgical procedure and the use of a of high-dose immunosuppressive living-donor pancreas transplants from a center have been the 1-yr pancreas, kidney, and patient survival rates were 95, and 95%, respectively However, to the and potential risks to the recipient the may this complications and attributable to to after kidney transplantation require further evaluation. considered for PAKT should undergo appropriate evaluation of their transplant and In levels, and should be in an immunologic to appropriate organ In for PAKT may the pancreas donor not only with the recipient but also with the previous kidney donor The of disease remains a The timing of PAKT must be on an individual on donor and recipient Despite these from donors for PAKT recipients the cadaveric recipient between and Pancreas Transplantation on transplant that the of pancreas transplantation are not that after kidney transplantation may some recipients from receiving PAKT. include the immunologic renal or donor vascular or cardiovascular heart or vascular and rejection is associated with long-term kidney graft survival rates is not patients who experience an acute rejection after kidney transplantation may greater to acute rejection after PAKT. are also by acute rejection with kidney because of renal or donor vascular should be for PAKT with PAKT is in the presence of acute as or or of diabetic complications, as and cerebrovascular should be the benefits of pancreas transplantation. who experience significant in cardiac and those with cerebrovascular with or vascular disease that is not to should not be considered for PAKT. In general, patients with those at higher risk for graft and those with complications should be from PAKT. The success rates for pancreas transplantation to in because of refinements in surgical The surgical procedure of three as the pancreas is and the to and from the pancreas graft is the exocrine drainage is These techniques are not different from those for SPKT. The management of pancreatic exocrine secretions a surgical and is a potential cause of complications after transplantation. Historically, the urinary bladder has been the preferred for drainage of exocrine secretions from the transplanted pancreas drainage the measurement of urinary amylase for a for monitoring of pancreatic graft and diagnosis of However, this can be associated with several complications, as pancreatitis, urinary bladder urinary and the pancreatic exocrine secretions can be the This has in and has been by an increasing number of transplant centers According to recent data from the of SPKT, of PAKT, and of PTA are (1). of this procedure include graft vascular thrombosis, and data that enteric drainage is a alternative to bladder drainage for pancreas However, enteric drainage has been for pancreas transplants with kidney transplants from the same In cases, the measurement of urinary amylase is not for the diagnosis of rejection, because renal monitoring on the immunologic status of the recipient. In bladder drainage has been considered the surgical of choice for PAKT, because urinary amylase monitoring remains a for the of rejection Moreover, there is some evidence that solitary pancreas transplantation with enteric exocrine drainage, with of may be associated with rejection and immunologic graft loss rates, with other transplantation techniques for PAKT The number of immunosuppressive available for pancreas transplant recipients has increased in the past yr. The IPTR reported allograft survival rates associated with immunosuppressive for patients who PAKT between and 1999 before and of (1). The results are in Table of PAKT recipients were given for patients reported to the IPTR at the and early of immunosuppression. patients who therapy, the 1-yr pancreas graft survival rates, to the immunosuppressive were as There was a better survival rates with the For patients who not undergo the 1-yr pancreas graft survival rates were as In the IPTR analysis that the use of therapy was associated with higher 1-yr pancreas graft survival In the combination of and a higher 1-yr pancreas graft survival Although these data must be in a it may be to a because of the number of at center and the high immunologic risks associated with PAKT. at higher has been associated with impaired glucose may be for this Table One-year pancreas graft survival rates after PAKT to there has been no experience with immunosuppression among PAKT recipients. However, a recent of an of SPKT recipients low rates of allograft rejection among patients who in combination with low of with the recent of successful islet transplantation using and it that the use of and steroid in the treatment of PAKT recipients will in the next few after PAKT of the pancreas transplant for rejection is an of management and is important after PAKT. With SPKT, the clinical of kidney transplant rejection usually pancreas the can be as a of rejection and the need for of the pancreas transplant for PAKT recipients is more because as amylase levels, levels, and of other pancreatic are The development of hyperglycemia is a particularly of rejection and is usually of a rejection The routine use of can also be associated with which may the diagnosis of have been for and diagnosis of pancreas The most are measurement of amylase and for pancreas transplants, measurement of urinary amylase amylase or suggest possible rejection but poor and for of other as and pancreatic become pancreas transplant rejection, but are not available and are not to the use of amylase or for the diagnosis of rejection The use of methods as with and for the diagnosis of rejection has also been Although of these excellent of the pancreas, the diagnostic is poor and the utility for the diagnosis of rejection is not well Finally, the glucose rate after glucose has been to greater and than either urinary amylase or for the diagnosis of rejection among patients receiving but not The for the diagnosis of pancreas rejection is now pancreas biopsy major have been developed for the diagnosis of rejection, and percutaneous biopsy with biopsy is only for pancreas transplants and requires of the bladder for of pancreatic biopsy is the of choice and is a to (10). can be for enteric and pancreas A was by of rejection from to and is based on the presence of or and The was observed to the to or of PAKT The benefits of after SPKT have been well However, benefits observed after PAKT have not been well This lack is attributable to the that fewer PAKT are performed at a recent in has with immunosuppressive as and is to the observed after SPKT to PAKT. Most of the that to demonstrate a with respect to and with of among diabetic patients who SPKT the early of and those who not undergo therapy before transplantation, with of among diabetic patients who kidney transplants only patients who SPKT significant improvements in heart rate with diabetic patients who kidney transplantation only was to improve among recipients who SPKT, with diabetic patients who only kidney transplants has also been to with long-term glucose be to the development of diabetic nephropathy, as in the Diabetes and was after 10 yr of normoglycemia after established of diabetic nephropathy be with in and and in the have been to improve after SPKT, with diabetic patients who only kidney transplants has been that among patients with poor and a number of have in most after SPKT, with in and and improved of diabetic recipients of SPKT kidney transplants alone have reported improvements in including function, and is that recipients who undergo PAKT will also experience these has been reported that SPKT recipients increased early rates, with diabetic patients who only kidney transplants However, those were and the results may be to the of SPKT. With long-term monitoring, rates were the same from in and rates after SPKT, with kidney transplants However, those experienced in appropriate SPKT recipients with grafts functioning were with patients who had either or their pancreas transplants recipients who in a SPKT were performed were with patients in a different transplants were performed be a SPKT kidney transplantation treatment of patients on the same transplant A recent analysis by the patient survival rates for living-donor transplants and cadaveric SPKT with cadaveric donor transplants Patient rates were higher after SPKT; the relative risk of death by yr was with living-donor and cadaveric donor transplantation. data for PAKT are not The of hyperglycemia associated with PAKT should have effects on survival rates, as well as diabetic However, this remains to be with a patient as that of the In the pancreas transplantation should the most for diabetic recipients to insulin The major of PAKT, with SPKT, is the ability to use a kidney from a by successful cadaveric pancreas transplantation. an does not have a effect on the cadaveric donor pool for kidney transplant recipients. of successful islet transplantation for using and have interest islet transplantation eliminates the need for a major surgical procedure, with its potential These results have not been at other and long-term monitoring is In the use of a donor for the pancreas transplant remains a of transplantation, with islet transplantation. this the clinical results of PAKT the use of the procedure for diabetic kidney transplant recipients. In the and total number of PAKT performed have steadily increased in recent because of a number of factors. (1) The results have continued to improve with advances in immunosuppressive therapy current 1-yr pancreas graft survival rate for PAKT recipients who undergo in with and therapy is (1). (2) Living-donor kidney transplantation by PAKT the kidney donor pool and transplantation as a (3) for PAKT are much than those for SPKT. the number of solitary pancreas transplants may improve donor and